Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo.

Abstract

Interactions between the proteasome inhibitor carfilzomib and the histone deacetylase (HDAC) inhibitors vorinostat and SNDX-275 were examined in mantle cell lymphoma (MCL) cells in vitro and in vivo. Coadministration of very low, marginally toxic carfilzomib concentrations (e.g., 3-4 nmol/L) with minimally lethal vorinostat or SNDX-275 concentrations induced sharp increases in mitochondrial injury and apoptosis in multiple MCL cell lines and primary MCL cells. Enhanced lethality was associated with c-jun-NH,-kinase (JNK) 1/2 activation, increased DNA damage (induction of λH2A.X), and ERK1/2 and AKT1/2 inactivation. Coadministration of carfilzomib and histone deacetylase inhibitors (HDACI) induced a marked increase in reactive oxygen species (ROS) generation and G(2)-M arrest. Significantly, the free radical scavenger tetrakis(4-benzoic acid) porphyrin (TBAP) blocked carfilzomib/HDACI-mediated ROS generation, λH2A.X formation, JNK1/2 activation, and lethality. Genetic (short hairpin RNA) knockdown of JNK1/2 significantly attenuated carfilzomib/HDACI-induced apoptosis, but did not prevent ROS generation or DNA damage. Carfilzomib/HDACI regimens were also active against bortezomib-resistant MCL cells. Finally, carfilzomib/vorinostat coadministration resulted in a pronounced reduction in tumor growth compared with single agent treatment in an MCL xenograft model associated with enhanced apoptosis, λH2A.X formation, and JNK activation. Collectively, these findings suggest that carfilzomib/HDACI regimens warrant attention in MCL.

• Authors: Girija Dasmahapatra, Dmitry Lembersky, Minkyeong P Son, Elisa Attkisson, Paul Dent, Richard I Fisher, Jonathan W Friedberg, Steven Grant
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 9 Pg. 1686-97 (Sep 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21750224 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Histone Deacetylase Inhibitors
• Histones
• Hydroxamic Acids
• Oligopeptides
• Vorinostat
• carfilzomib
• Superoxide Dismutase
• superoxide dismutase 2
• Oncogene Protein v-akt
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 4
• Caspases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Drug Synergism
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Histones (metabolism)
• Humans
• Hydroxamic Acids (pharmacology, therapeutic use)
• Lymphoma, Mantle-Cell (drug therapy, metabolism)
• MAP Kinase Kinase 4 (metabolism)
• Mice
• Mice, Nude
• Oligopeptides (pharmacology, therapeutic use)
• Oncogene Protein v-akt (metabolism)
• Phosphorylation (drug effects)
• Superoxide Dismutase (metabolism)
• Vorinostat